Pyridine Carboxamide orexin Receptor Antagonists

ABSTRACT

The present invention is directed to pyridyl carboxamide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell,1998, 92, 573-585). Orexins are found to stimulate food consumption inrats suggesting a physiological role for these peptides as mediators inthe central feedback mechanism that regulates feeding behaviour (SakuraiT. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX 1 receptor and OX 2receptor as the two subtypes of orexin receptors.

Orexin receptors are found in the mammalian brain and may have numerousimplications in pathologies such as depression; anxiety; addictions;obsessive compulsive disorder; affective neurosis; depressive neurosis;anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder;sexual dysfunction; psychosexual dysfunction; sex disorder;schizophrenia; manic depression; delirium; dementia; severe mentalretardation and dyskinesias such as Huntington's disease and Tourettesyndrome; eating disorders such as anorexia, bulimia, cachexia,dysregulated appetite control; obesity; addictive feeding behaviors;binge/purge feeding behaviors; cardiovascular diseases; diabetes;appetite, taste, eating or drinking disorders; emesis, vomiting, nausea;asthma; cancer; Parkinson's disease; Cushing's syndrome/disease;basophile adenoma; prolactinoma; hyperprolactinemia; hypophysistumour/adenoma; hypothalamic diseases; inflammatory bowel disease;gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; disturbed biological andcircadian rhythms; sleep disturbances associated with diseases such asneurological disorders, neuropathic pain and restless leg syndrome;heart and lung diseases, acute and congestive heart failure;hypotension; hypertension; urinary retention; osteoporosis; anginapectoris; myocardinal infarction; ischemic or haemorrhagic stroke;subarachnoid haemorrhage; ulcers; allergies; benign prostatichypertrophy; chronic renal failure; renal disease; impaired glucosetolerance; migraine; hyperalgesia; pain; enhanced or exaggeratedsensitivity to pain such as hyperalgesia, causalgia, and allodynia;acute pain; burn pain; atypical facial pain; neuropathic pain; backpain; complex regional pain syndrome I and II; arthritic pain; sportsinjury pain; pain related to infection e.g. HIV, post-chemotherapy pain;post-stroke pain; post-operative pain; neuralgia; conditions associatedwith visceral pain such as irritable bowel syndrome, and angina; urinarybladder incontinence e.g. urge incontinence; tolerance to narcotics orwithdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy;insomnia; parasomnia; jet lag syndrome; and neurodegenerative disordersincluding nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders and otherdiseases related to general orexin system dysfunction.

Certain orexin receptor antagonists are disclosed in PCT patentpublications WO 99/09024, WO 99/58533, WO 00/47576, WO 00/47577, WO00/47580, WO 01/68609, WO 01/85693, WO 01/96302, WO 2002/044172, WO2002/051232, WO 2002/051838, WO 2002/089800, WO 2002/090355, WO2003/002559, WO 2003/002561, WO 2003/032991, WO 2003/037847, WO2003/041711, WO 2003/051368, WO 2003/051872, WO 2003/051873, WO2004/004733, WO 2004/026866, WO 2004/033418, WO 2004/041807, WO2004/041816, WO 2004/052876, WO 2004/083218, WO 2004/085403, WO2004/096780, WO 2005/060959, WO 2005/075458, WO2005/118548, WO2006/067224, WO 2006/110626, WO 2006/127550, WO 2007/019234, WO2007/025069, WO 2007/061763, WO 2007/116374, WO 2007/122591, WO2007/126934, WO 2007/126935, WO 2008/008517, WO 2008/008518, WO2008/008551, WO 2008/020405, WO 2008/026149, WO 2008/038251.

SUMMARY OF THE INVENTION

The present invention is directed to pyridyl carboxamide compounds whichare antagonists of orexin receptors, and which are useful in thetreatment or prevention of neurological and psychiatric disorders anddiseases in which orexin receptors are involved. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which orexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A¹ is selected from the group consisting of phenyl, naphthyl andheteroaryl;A² is selected from the group consisting of phenyl, naphthyl andheteroaryl;A³ is selected from the group consisting of phenyl, naphthyl,C₃₋₆cycloalkyl, and heterocycle;R^(1a), R^(1b) and R^(1c) may be absent if the valency of A¹ does notpermit such substitution and are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R¹³,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R¹³,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R¹³,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R¹³,        -   (f) phenyl, which is unsubstituted or substituted with R¹³,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R¹³,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R^(2a), R^(2b) and R^(2c) may be absent if the valency of A²        does not permit such substitution and are independently selected        from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R^(3a), R^(3b) and R^(3c) may be absent if the valency of A³        does not permit such substitution and are independently selected        from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        with the proviso that if A³ is pyridyl, at least one of R^(3a),        R^(3b) and R^(3c) is other than hydrogen;        R⁴ and R⁵ are independently selected from hydrogen and        C₁₋₆alkyl, which is unsubstituted or substituted with one or        more substituents selected from R¹³, or R⁴ and R⁵ may be joined        together to form a C₃₋₆cycloalkyl with the carbon atom to which        they are attached, where the cycloalkyl is unsubstituted or        substituted with one or more substituents selected from R¹³;        R⁶ is hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl, which is        unsubstituted or substituted with one or more substituents        selected from R¹³;        R¹³ is selected from the group consisting of:    -   (1) halogen,    -   (2) hydroxyl,    -   (3) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (4) —O_(n)—(C₁₋₃)perfluoroalkyl,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R¹⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH—C₁₋₆alkyl,    -   (8) phenyl,    -   (9) heterocycle,    -   (10) —CO₂H, and    -   (11) —CN;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein A¹, A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c),R^(3a), R^(3b), R^(3c) and R⁴ are defined herein;or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein A¹, A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c),R^(3a), R^(3b) and R^(3c) are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIc′:

wherein A², A³, R^(1a), R^(1b), R^(2a), R^(2b), R^(2c), R^(3a), R^(3b)and R^(3c) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaId:

wherein A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaId′:

wherein A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIe:

wherein A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIf:

wherein A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIg:

wherein A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIh:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIi:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIj:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a)and R^(3b) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaIk:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a)and R^(3b) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaIl:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b) and R^(2c) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIm:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b) and R^(2c) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein A¹ isphenyl. An embodiment of the present invention includes compoundswherein A¹ is naphthyl. An embodiment of the present invention includescompounds wherein A¹ is heteroaryl. An embodiment of the presentinvention includes compounds wherein A¹ is pyridyl.

An embodiment of the present invention includes compounds wherein A² isphenyl. An embodiment of the present invention includes compoundswherein A² is naphthyl. An embodiment of the present invention includescompounds wherein A² is heteroaryl. An embodiment of the presentinvention includes compounds wherein A² is quinoxalinyl. An embodimentof the present invention includes compounds wherein A² is pyridyl. Anembodiment of the present invention includes compounds wherein A² ispyrazinyl. An embodiment of the present invention includes compoundswherein A² is quinolinyl. An embodiment of the present inventionincludes compounds wherein A² is indolyl. An embodiment of the presentinvention includes compounds wherein A² is dihydroindolyl. An embodimentof the present invention includes compounds wherein A² isbenzimidazolyl.

An embodiment of the present invention includes compounds wherein A³ ispyrazolyl. An embodiment of the present invention includes compoundswherein A³ is pyrazolyl which is substituted with methyl. An embodimentof the present invention includes compounds wherein A³ is pyridyl, whichis substituted with at least one substituent other than hydrogen. Anembodiment of the present invention includes compounds wherein A³ ispyridyl, which is substituted with fluroro or chloro. An embodiment ofthe present invention includes compounds wherein A³ is phenyl. Anembodiment of the present invention includes compounds wherein A³ isphenyl, which is substituted with at least one substituent other thanhydrogen. An embodiment of the present invention includes compoundswherein A³ is phenyl, which is substituted with hydroxyl,methylaminocarbonyl or dimethylaminomethyl. An embodiment of the presentinvention includes compounds wherein A³ is cyclopentyl. An embodiment ofthe present invention includes compounds wherein A³ is morpholinyl. Anembodiment of the present invention includes compounds wherein A³ ispyrrolidinyl. An embodiment of the present invention includes compoundswherein A³ is azetidinyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl, and    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen, and    -   (3) C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluroro, and    -   (4) methyl.

An embodiment of the present invention includes compounds wherein A¹ isphenyl and R^(1a), R^(1b) and R^(1c) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluroro, and    -   (4) methyl.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (6) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, and    -   (5) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methoxy,    -   (6) t-butoxy,    -   (7) difluoromethyl, and    -   (8) trifluoromethyl,    -   (9) —N(CH₃).

An embodiment of the present invention includes compounds wherein A² isphenyl and R^(2a), R^(2b) and R^(2c) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methoxy,    -   (6) t-butoxy,    -   (7) difluoromethyl, and    -   (8) trifluoromethyl,    -   (9) —N(CH₃).

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂;        with the proviso that if A³ is pyridyl, at least one of R^(3a),        R^(3b) and R^(3c) is other than hydrogen.

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl, and    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl;        with the proviso that if A³ is pyridyl, at least one of R^(3a),        R^(3b) and R^(3c) is other than hydrogen.

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen, and    -   (3) C₁₋₆alkyl;        with the proviso that if A³ is pyridyl, at least one of R^(3a),        R^(3b) and R^(3c) is other than hydrogen.

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluroro, and    -   (4) methyl;        with the proviso that if A³ is pyridyl, at least one of R^(3a),        R^(3b) and R^(3c) is other than hydrogen.

An embodiment of the present invention includes compounds wherein A³ ispyridyl and wherein R^(3a) is halogen, R^(3b) is hydrogen and R^(3c) ishydrogen. An embodiment of the present invention includes compoundswherein A³ is pyridyl and wherein R^(3a) is chloro or fluoro, R^(3b) ishydrogen and R^(3c) is hydrogen.

An embodiment of the present invention includes compounds wherein A³ ispyrazolyl and wherein R^(3a) is C₁₋₆alkyl, R^(3b) is hydrogen and R^(3c)is hydrogen. An embodiment of the present invention includes compoundswherein A³ is pyrazolyl and wherein R^(3a) is methyl, R^(3b) is hydrogenand R^(3c) is hydrogen.

An embodiment of the present invention includes compounds wherein R⁴ ishydrogen or C₁₋₆alkyl. An embodiment of the present invention includescompounds wherein R⁴ is hydrogen or methyl. An embodiment of the presentinvention includes compounds wherein R⁴ is hydrogen. An embodiment ofthe present invention includes compounds wherein R⁵ is hydrogen orC₁₋₆alkyl. An embodiment of the present invention includes compoundswherein R⁵ is hydrogen or methyl. An embodiment of the present inventionincludes compounds wherein R⁵ is hydrogen.

An embodiment of the present invention includes compounds wherein R⁶ ishydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl. An embodiment of the presentinvention includes compounds wherein R⁶ is C₁₋₆alkyl. An embodiment ofthe present invention includes compounds wherein R⁶ is C₃₋₆cycloalkyl.An embodiment of the present invention includes compounds wherein R⁶ ishydrogen, methyl or ethyl. An embodiment of the present inventionincludes compounds wherein R⁶ is hydrogen.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizing orexinreceptor activity in a patient such as a mammal in need of suchinhibition comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. In additionto primates, especially humans, a variety of other mammals can betreated according to the method of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for antagonizing orexin receptor activity ortreating the disorders and diseases noted herein in humans and animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of” and or “administering a”compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need thereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat orexin-1 receptor or the human orexin-2 receptor, aregrown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/mlG418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). Thecells are seeded at 20,000 cells/well into Becton-Dickinson black384-well clear bottom sterile plates coated with poly-D-lysine. Allreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as theagonist is prepared as a 1 mM stock solution in 1% bovine serum albumin(BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSAand 2.5 mM probenecid, pH7.4) for use in the assay at a finalconcentration of 70 pM. Test compounds are prepared as 10 mM stocksolution in DMSO, then diluted in 384-well plates, first in DMSO, thenassay buffer. On the day of the assay, cells are washed 3 times with 100ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ulassay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1%BSA. The dye loading solution is then aspirated and cells are washed 3times with 100 ul assay buffer. 30 ul of that same buffer is left ineach well. Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), test compounds are added to the plate in a volume of 25 ul,incubated for 5 min and finally 25 ul of agonist is added. Fluorescenceis measured for each well at 1 second intervals for 5 minutes and theheight of each fluorescence peak is compared to the height of thefluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer inplace of antagonist. For each antagonist, IC50 value (the concentrationof compound needed to inhibit 50% of the agonist response) isdetermined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant(K_(i)) is determined in membranes prepared from CHO cells expressingeither the OX1 or OX2 receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

In particular, the compounds of the following examples had activity inantagonizing the rat orexin-1 receptor and/or the human orexin-2receptor in the aforementioned assays, generally with an IC₅₀ of lessthan about 50 μM. Many of compounds within the present invention hadactivity in antagonizing the rat orexin-1 receptor and/or the humanorexin-2 receptor in the aforementioned assays with an IC₅₀ of less thanabout 100 nM. Compounds of the present invention also have activity inthe radioligand binding assay, generally with a Ki <100 nM against theorexin-1 and/or the orexin-2 receptor. Additional data is provided inthe following Examples. Such a result is indicative of the intrinsicactivity of the compounds in use as antagonists of orexin-1 receptorand/or the orexin-2 receptor. The present invention also includescompounds within the generic scope of the invention which possessactivity as agonists of the orexin-1 receptor and/or the orexin-2receptor. With respect to other pyridyl compounds, the present compoundsexhibit unexpected properties, such as with respect to increased oralbioavailability, metabolic stability, decreased inhibition of metabolicenzymes (such as decreased cytochrome P450 3A4 (CYP3A4) inhibition),decreased inhibition of transporters (such as decreasedp-glycoprotein/PGP inhibition) and/or selectivity with respect to otherreceptors, including the human orexin-2 receptor.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention have utility in treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with orexin receptors,including one or more of the following conditions or diseases: sleepdisorders, sleep disturbances, including enhancing sleep quality,improving sleep quality, increasing sleep efficiency, augmenting sleepmaintenance; increasing the value which is calculated from the time thata subject sleeps divided by the time that a subject is attempting tosleep; improving sleep initiation; decreasing sleep latency or onset(the time it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing intermittent wakings during sleep; decreasingnocturnal arousals; decreasing the time spent awake following theinitial onset of sleep; increasing the total amount of sleep; reducingthe fragmentation of sleep; altering the timing, frequency or durationof REM sleep bouts; altering the timing, frequency or duration of slowwave (i.e. stages 3 or 4) sleep bouts; increasing the amount andpercentage of stage 2 sleep; promoting slow wave sleep; enhancingEEG-delta activity during sleep; decreasing nocturnal arousals,especially early morning awakenings; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersincluding overeating and bulimia nervosa, hypertension, diabetes,elevated plasma insulin concentrations and insulin resistance,dyslipidemias, hyperlipidemia, endometrial, breast, prostate and coloncancer, osteoarthritis, obstructive sleep apnea, cholelithiasis,gallstones, heart disease, abnormal heart rhythms and arrythmias,myocardial infarction, congestive heart failure, coronary heart disease,sudden death, stroke, polycystic ovary disease, craniopharyngioma, thePrader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects,normal variant short stature, Turner's syndrome, and other pathologicalconditions showing reduced metabolic activity or a decrease in restingenergy expenditure as a percentage of total fat-free mass, e.g, childrenwith acute lymphoblastic leukemia, metabolic syndrome, also known assyndrome X, insulin resistance syndrome, reproductive hormoneabnormalities, sexual and reproductive dysfunction, such as impairedfertility, infertility, hypogonadism in males and hirsutism in females,fetal defects associated with maternal obesity, gastrointestinalmotility disorders, intestinal motility dyskinesias, obesity-relatedgastro-esophageal reflux, hypothalmic diseases, hypophysis diseases,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), breathlessness, cardiovascular disorders,inflammation, such as systemic inflammation of the vasculature,arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain,gallbladder disease, gout, kidney cancer, increased anesthetic risk,reducing the risk of secondary outcomes of obesity, such as reducing therisk of left ventricular hypertrophy; diseases or disorders whereabnormal oscillatory activity occurs in the brain, including depression,migraine, neuropathic pain, Parkinson's disease, psychosis andschizophrenia, as well as diseases or disorders where there is abnormalcoupling of activity, particularly through the thalamus; enhancingcognitive function, including cognitive dysfunctions that comprisedeficits in all types of attention, learning and memory functionsoccurring transiently or chronically in the normal, healthy, young,adult or aging population, and also occurring transiently or chronicallyin psychiatric, neurologic, cardiovascular and immune disorders;enhancing memory; increasing memory retention; increasing immuneresponse; increasing immune function; hot flashes; night sweats;extending life span; schizophrenia; muscle-related disorders that arecontrolled by the excitation/relaxation rhythms imposed by the neuralsystem such as cardiac rhythm and other disorders of the cardiovascularsystem; conditions related to proliferation of cells such asvasodilation or vasorestriction and blood pressure; cancer; cardiacarrhythmia; hypertension; congestive heart failure; conditions of thegenital/urinary system; disorders of sexual function and fertility;adequacy of renal function; responsivity to anesthetics; mood disorders,such as depression or more particularly depressive disorders, forexample, single episodic or recurrent major depressive disorders anddysthymic disorders, or bipolar disorders, for example, bipolar Idisorder, bipolar II disorder and cyclothymic disorder, mood disordersdue to a general medical condition, and substance-induced mooddisorders; anxiety disorders including acute stress disorder,agoraphobia, generalized anxiety disorder, obsessive-compulsivedisorder, panic attack, panic disorder, post-traumatic stress disorder,separation anxiety disorder, social phobia, specific phobia,substance-induced anxiety disorder and anxiety due to a general medicalcondition; acute neurological and psychiatric disorders such as cerebraldeficits subsequent to cardiac bypass surgery and grafting, stroke,ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma,perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage;Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis;ocular damage; retinopathy; cognitive disorders; idiopathic anddrug-induced Parkinson's disease; muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, seizure disorders, absence seisures, complex partial andgeneralized seizures; Lennox-Gastaut syndrome; cognitive disordersincluding dementia (associated with Alzheimer's disease, ischemia,trauma, vascular problems or stroke, HIV disease, Parkinson's disease,Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease,perinatal hypoxia, other general medical conditions or substance abuse);delirium, amnestic disorders or age related cognitive decline;schizophrenia or psychosis including schizophrenia (paranoid,disorganized, catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced psychotic disorder; dissociateivedisorders including multiple personality syndromes and psychogenicamnesias; substance-related disorders, substance use, substance abuse,substance seeking, substance reinstatement, all types of psychologicaland physical addictions and addictive behaviors, reward-relatedbehaviors (including substance-induced delirium, persisting dementia,persisting amnestic disorder, psychotic disorder or anxiety disorder;tolerance, addictive feeding, dependence, withdrawal or relapse fromsubstances including alcohol, amphetamines, cannabis, cocaine,hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine,sedatives, hypnotics or anxiolytics); movement disorders, includingakinesias and akinetic-rigid syndromes (including Parkinson's disease,drug-induced parkinsonism, postencephalitic parkinsonism, progressivesupranuclear palsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),chronic fatigue syndrome, fatigue, including Parkinson's fatigue,multiple sclerosis fatigue, fatigue caused by a sleep disorder or acircadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); attentiondeficit/hyperactivity disorder (ADHD); conduct disorder; migraine(including migraine headache); headache; hyperalgesia; pain; enhanced orexaggerated sensitivity to pain such as hyperalgesia, causalgia, andallodynia; acute pain; burn pain; atypical facial pain; neuropathicpain; back pain; complex regional pain syndrome I and II; arthriticpain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); conditions associated with visceral painsuch as irritable bowel syndrome, and angina; eating disorders; urinaryincontinence; substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis;schizophrenia; anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder); mood disorders (includingdepression, mania, bipolar disorders); trigeminal neuralgia; hearingloss; tinnitus; neuronal damage including ocular damage; retinopathy;macular degeneration of the eye; emesis; brain edema; pain, includingacute and chronic pain states, severe pain, intractable pain,inflammatory pain, neuropathic pain, post-traumatic pain, bone and jointpain (osteoarthritis), repetitive motion pain, dental pain, cancer pain,myofascial pain (muscular injury, fibromyalgia), perioperative pain(general surgery, gynecological), chronic pain, neuropathic pain,post-traumatic pain, trigeminal neuralgia, migraine and migraineheadache.

Thus, in specific embodiments the present invention provides methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of acompound of the present invention.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein. The dosage of active ingredientin the compositions of this invention may be varied, however, it isnecessary that the amount of the active ingredient be such that asuitable dosage form is obtained. The active ingredient may beadministered to patients (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. perpatient per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; and in yet another embodiment about 5 mg to 50 mg perpatient per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 Hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includestherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: insulin sensitizers including (i) PPARγantagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor α agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB₁ receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosedescribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors ((3-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone

agonists, such as KB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase)inhibitors, such as Cerulenin and C75; (39) DGAT1 (diacylglycerolacyltransferase 1) inhibitors; (40) DGAT2 (diacylglycerolacyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2)inhibitors; (42) glucocorticoid antagonists; (43) acyl-estrogens, suchas oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., ObesityResearch, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP-IV)inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011,P9310/K364, VIP 0177, SDZ 274-444, sitagliptin; and the compoundsdisclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO 03/004496; EP 1258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181;(46) dicarboxylate transporter inhibitors; (47) glucose transporterinhibitors; (48) phosphate transporter inhibitors; (49) Metformin(Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY, PYY 3-36,peptide YY analogs, derivatives, and fragments such as BIM-43073D,BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci. 44(3):643-48 (1999));(51) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl[Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide, (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H₃ antagonists; AMPAagonists; PDE IV inhibitors; GABA_(A) inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein. The following abbreviations are used herein: Me: methyl; Et:ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl;ACN: acetonitrile; THF: tetrahydrofuran; DEAD: diethylazodicarboxylate;DIPEA: N,N-diisopropylethylamine; NMM: N-methylmorpholine; DMSO:dimethylsulfoxide; EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide;HOBT: hydroxybenzotriazole hydrate; Boc: tert-butyloxy carbonyl; Et₃N:triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovineserum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide;MTBE: methyl tert-butyl ether; SOCl₂: thionyl chloride; CDI: carbonyldiimidazole; PyClu: 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidiniumhexafluorophosphate; T3P: 1-propylphosphonic acid cyclic anhydride; rt:room temperature; HPLC: high performance liquid chromatography. Thecompounds of the present invention can be prepared in a variety offashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

5-Aryl-2-chloronicotinic acids (A-2) are synthesized via Suzuki couplingreactions on A-1 with aryl boronic under standard conditions followed byhydrolysis. A-2 are coupled to amines using PyClu to give A-3. Couplingof A-3 with boronic acids using standard Suzuki coupling conditionsunder microwave heating affords A-4.

2,5-Disubstituted nicotinic acids (B-2) can be synthesized via B-1 byselective Suzuki coupling on the 5-position followed by another Suzukicoupling on the 2-position and in situ hydrolysis. Compounds such as B-2can be advanced to final compounds through amide coupling to afford B-3.

2,5-Disubstituted nicotinic acids (C-2) can be synthesized via C-1 byselective Suzuki coupling on the 5-position followed by another Suzukicoupling on the 2-position followed by basic hydrolysis. Compounds suchas C-2 can be advanced to final compounds through amide coupling toafford C-3.

2,5-Disubstituted nicotinic acids (D-2) can be synthesized via D-1 byselective Suzuki coupling on the 5-position followed by nucleophilicsubstitution on the 2-position and hydrolysis of the ester. Compoundssuch as D-2 can be advanced to final compounds through amide coupling toafford D-3.

2,5-Disubstituted nicotinic acids (E-2) can be synthesized via E-1 byselective Suzuki coupling on the 5-position followed by nucleophilicsubstitution with N—H containing heterocycles on the 2-position.Hydrolysis of the ester affords E-2. Compounds such as E-2 can beadvanced to final compounds through amide coupling to afford E-3.

2,5-Disubstituted nicotinic acids (F-2) can be synthesized via F-1 byselective Suzuki coupling on the 5-position followed by Negishi couplingon the 2-position. Hydrolysis of the ester affords F-2. Compounds suchas F-2 can be advanced to final compounds through amide coupling toafford F-3.

2,5-Disubstituted nicotinic esters (G-2) can be synthesized via G-1 byselective Stille coupling on the 5-position followed by another Stillecoupling on the 2-position. Compounds such as G-2 can be advanced tofinal compounds through transamination mediated by trimethylaluminum toafford G-3.

2,5-Disubstituted nicotinic acids (H-2) can be synthesized via F-1 byselective Suzuki coupling on the 5-position followed by Stille couplingon the 2-position. Hydrolysis of the ester affords H-2. Compounds suchas H-2 can be advanced to final compounds through amide coupling toafford H-3.

Example 1

2-Chloro-5-(3,5-dimethylphenyl)nicotinic acid (1-2)

To a deoxygenated solution of methyl 2-chloro-5-iodonicotinate (1-1,2.01 g, 6.72 mmol, 1 equiv) and 3,5-dimethylphenylboronic acid (1.01 g,6.72 mmol. 1.00 equiv) in dioxane (250 mL) was addedtetrakis(triphenylphosphine)palladium(0) (155 mg, 0.134 mmol) and 2 Naqueous sodium bicarbonate solution (16.8 mL, 33.6 mmol, 5.00 equiv) andthe reaction mixture was heated at 90° C. for 48 hours. The reactionmixture was allowed to cool to 23° C., then partitioned between ethylacetate (500 mL) and saturated aqueous sodium bicarbonate solution (500mL). The aqueous layer was filtered and acidified to pH 2 withconcentrated hydrochloric acid. The resulting precipitate was collectedby filtration washed with water (2×100 mL) and air dried to afford2-chloro-5-(3,5-dimethylphenyl)nicotinic acid (1-2) as an off whitesolid. LRMS m/z (M+H) 262.3 found, 262.1 required.

2-Chloro-N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)nicotinamide(1-3)

To a solution of 2-chloro-5-(3,5-dimethylphenyl)nicotinic acid (1-2,0.200 g, 0.764 mmol, 1 equiv) and 3,4-dimethoxybenzylamine (0.319 g,1.91 mmol, 2.50 equiv) in DMF (5 mL) was added1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate(PyClu, 0.383 mg, 1.15 mmol, 1.51 equiv), and diisopropylethylamine(0.667 mL, 3.82 mmol, 5.00 equiv). The resulting mixture was stirred at23° C. for 20 hours. The reaction mixture was filtered and purified viareverse phase liquid chromatography (H₂O/CH₃CN gradient w/0.1% TFApresent). The desired fractions were partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine then dried over sodiumsulfate and concentrated to give2-chloro-N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)nicotinamide(1-3) as a white powder. LRMS m/z (M+H) 262.3 found, 262.1 required.

N-(3,4-Dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide(1-4)

To a solution of2-chloro-N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)nicotinamide(1-3, 50.0 mg, 0.122 mmol)) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(25.3 mg, 0.122 mmol) in dioxanes (3 mL) was addedtetrakis(triphenylphosphine)palladium(0) (7.03 mg, 6.08 μmol) and 2 Naqueous sodium bicarbonate solution (0.304 mL, 0.608 mmol). Undermicrowave heating the deoxygenated mixture was held at 160° C. for 1 h.The reaction mixture was filtered and concentrated to dryness. A solidresidue was triturated with ethyl acetate (4 mL), collected byfiltration, washed with water (10 mL) and air dried to affordN-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide(1-4). ¹H NMR (300 MHz, DMSO) δ 9.09 (t, 1H, J=5.8 Hz), 8.87 (d, 1H,J=1.8 Hz), 7.92 (d, 1H, J=1.8 Hz), 7.82 (d, 1H, J=9.8 Hz), 7.39 (s, 2H),7.06 (s, 1H), 6.92 (m, 3H), 4.29 (d, 2H, J=5.3 Hz), 3.74 (m, 6H), 3.32(s, 3H), 2.35 (s, 3H). HRMS m/z (M+H) 457.2242 found, 457.2234 required.

TABLE 1 The following compounds were prepared using the foregoingmethodology, but substituting the appropriately substituted reagent, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis without undue experimentation. Cmp Structure Name HRMS m/z(M + H) 1-5 

N-(3,4-dimethoxybenzyl)-5- (3,5-dimethylphenyl)-6′-fluoro-2,3′-bipyridine-3- carboxamide 472.2025 found, 472.2031 required.1-6 

N-(3,4-dimethoxybenzyl)-5- (3,5-dimethylphenyl)-2-quinolin-3-ylnicotinamide 504.2286 found, 504.2282 required. 1-7 

N-(3,4-dimethoxybenzyl)-5- (3,5-dimethylphenyl)-2-(3-hydroxyphenyl)nicotinamide 469.2119 found, 469.2122 required. 1-8 

N-(3,4-dimethoxybenzyl)-5- (3,5-dimethylphenyl)-2-{3-[(methylamino)carbonyl] phenyl}nicotinamide 510.2406 found, 510.2388required. 1-9 

N-(3,4-dimethoxybenzyl)-2- {3-[(dimethylamino)methyl] phenyl}-5-(3,5-dimethylphenyl) nicotinamide 510.2748 found, 510.2753 required. 1-10

N-(3,4-dimethoxybenzyl)-5- (3,5-dimethylphenyl)-2-(1H-indol-5-yl)nicotinamide 492.2289 found, 492.2282 required. 1-11

5-(3,5-dimethylphenyl)-N- [(1R)-1-(3- methoxyphenyl)ethyl)-2-(1-methyl-1H-pyrazol-4- yl)nicotinamide 441.2298 found, 441.2285 required.1-12

5-(3,5-dimethylphenyl)-2-(1- methyl-1H-pyrazol-4-yl)-N-(quinolin-2-ylmethyl) nicotinamide 448.2138 found, 448.2132 required.1-13

N-[(5,6-dimethoxypyridin-3- yl)methyl]-5-(3,5-dimethylphenyl)-2-(1-methyl- 1H-pyrazol-4-yl)nicotinamide 458.2195found, 458.2187 required. 1-14

5-(3,5-dichlorophenyl)-N- [(2,3-dimethyl-1H-indol-6-yl)methyl]-2-(1-methyl-1H- pyrazol-4-yl)nicotinamide 504.1366 found,504.1353 required. 1-15

5-(3-fluoro-5-methylphenyl)- 2-(1-methyl-1H-pyrazol-4-yl)- N-[(1R)-1-(2-naphthyl)ethyl]nicotinamide 465.2098 found, 465.2085 required. 1-16

5-(3,5-dimethylphenyl)-2-(1- methyl-1H-pyrazol-4-yl)-N-(2-naphthylmethyl) nicotinamide 447.2190 found, 447.2180 required. 1-17

5-(3-fluoro-5-methylphenyl)- 2-(1-methyl-1H-pyrazol-4-yl)-N-(2-naphthylmethyl) nicotinamide 451.1944 found, 451.1929 required.1-18

5-(3,5-dimethylphenyl)-2-(1- methyl-1H-pyrazol-4-yl)-N- (quinolin-3-ylmethyl)nicotinamide 448.2134 found, 448.2132 required.

Example 2

5-(3-Chloro-5-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinic acid(2-2)

To a solution of methyl 2-chloro-5-iodonicotonate (2-1, 1.00 g, 3.36mmol) in dimethylformamide (15 mL) at 25° C. was added3-chloro-5-methylboronic acid (0.573 g, 3.36 mmol; synthesized viaprocedures found in Org. Lett. 2007, 9, 757-760), PdCl₂dppf (0.246 g,0.336 mmol) followed by 1M aqueous cesium carbonate (13.5 mL, 13.5 mmol)and the system was stirred for 4 h at 25° C. The system was partitionedbetween water and EtOAc, and dried over magnesium sulfate. Filtrationand concentration yielded a brown solid which upon tritiration withether afforded a tan solid. To this tan solid (0.05 g, 0.169 mmol) indimethylformamide (0.8 mL) at 25° C. was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole(0.038 g, 0.186 mmol), PdCl₂dppf (0.012 g, 0.017 mmol) followed by 4Maqueous cesium carbonate (0.67 mL, 0.675 mmol) and the system wasstirred for 15 minutes at 135° C. in the microwave. The system waspartitioned between water and EtOAc. The aqueous layer was thenacidified using 25% citric acid to a pH of 3, extracted with EtOAc andthe organic layer was dried over magnesium sulfate. Filtration andconcentration afforded the title compound (2-2) as a cream solid. ESI+MS[M+H]⁺C₁₇H₁₄ClN₃O₂=328.0.

5-(3-Chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide(2-3)

To a solution of5-(3-chloro-5-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinic acid(2-2, 0.050 g, 0.153 mmol) and 3,4-dimethoxybenzylamine (0.099 g, 0.595mmol) in dimethylformamide (1 mL) was added EDC (0.132 g, 0.686 mmol),HOBt (0.105 g, 0.686 mmol) followed by N-methylmorpholine (0.250 mL,2.28 mmol) and the system was stirred at 25° C. overnight. The reactionmixture was partitioned between ethyl acetate and water, washed withsaturated sodium carbonate and dried over magnesium sulfate. Thereaction mixture was filtered and purified via normal phasechromatography (0→5% MeOH in DCM) to afford the title compound (2-3) asa bone-colored powder. ¹H NMR (500 MHz, CDCl₃) δ 8.81 (d, J=2.5 Hz, 1H),7.99 (s, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 7.28(m, 2H), 7.23 (s, 1H), 6.84 (s, 2H), 6.06 (m, 1H), 4.55 (d, J=6 Hz, 2H),3.88 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 2.42 (s, 3H). HRMS [M+H]C₂₆H₂₅ClN₄O₃ calc'd 477.1688. Found 477.1682.

TABLE 2 The following compounds were prepared using the foregoingmethodology, but substituting the appropriately substituted reagent, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis without undue experimentation. Cmp Structure Name HRMS m/z(M + H) 2-4 

5-(3,5-fluoromethylphenyl)-N- [1-(3,4-dimethoxyphenyl)ethyl]-2-(1-methyl-1H- pyrazol-4-yl)nicotinamide 475.2128 found,475.2140 required. 2-5 

5-(3,5-fluoromethylphenyl)-N- (3,4-dimethoxybenzyl)-2-(1-methyl-1H-pyrazol-4- yl)nicotinamide 461.1962 found, 461.1984 required.2-6 

5-(3,5-chloromethylphenyl)- N-[(2,3-dimethyl-1-H-indol-5-yl)methyl]-2-(1-methyl-1H- pyrazol-4-yl)nicotinamide 484.1880 found,484.1899 required. 2-7 

5-(3,5-chloromethylphenyl)- N-(2-naphthylmethyl)-2-(1-methyl-1H-pyrazol-4- yl)nicotinamide HRMS m/z (M + H) 467.1643 found,467.1633 required. 2-8 

5-(3,5-fluoromethylphenyl)-N- (3,4-dimethoxybenzyl)-2-pyridazin-3yl-nicotinamide 459.1859 found, 459.1827 required. 2-9 

5-(3,5-chloromethylphenyl)- N-(3,4-dichlorobenzyl)-2-(1-methyl-1H-pyrazol-4- yl)nicotinamide 485.0706 found, 485.0697 required.2-10

5-(3,5-fluoromethylphenyl)-N- [1-(3,4-dimethoxyphenyl)ethyl]-6′-fluoro-2,3′- bipyridine-3-carboxamide 490.1916 found, 490.1937required. 2-11

5-(3,5-dichlorophenyl)-N- (3,4-dimethoxybenzyl)-5′-chloro-2,3′-bipyridine-3- carboxamide 528.0620 found, 528.0643 required.2-12

5-(3,5-chloromethylphenyl)- N-[(1-methyl-1H- benzimidazol-2-yl)methyl]-2- (1-methyl-1H-pyrazol-4- yl)nicotinamide 471.1711 found,471.1695 required. 2-13

5-(3,5-chloromethylphenyl)- N-[(1-methyl-2,3-dihydro-1H- indol-5-yl)methyl]-2-(1- methyl-1H-pyrazol-4- yl)nicotinamide 472.1915 found,472.1899 required. 2-14

5-(3,5-chloromethylphenyl)- N-[(1,4-dimethyl-1,2,3,4-tetrahydroquinoxalin-6-yl) methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide 480.1687 found, 480.1694 required. 2-15

5-(3,5-chloromethylphenyl)- N-[(1,4,5-trimethyl-1H-imidazol-2-yl)methyl]-2-(1- methyl-1H-pyrazol-4- yl)nicotinamide449.1850 found, 449.1851 required. 2-16

5-(3,5-fluoromethylphenyl)-N- (3,4-dimethoxybenzyl)-2-(1-methyl-1H-pyrazol-5- yl)nicotinamide 461.1995 found, 461.1984 required.2-17

5-(3,5-chloromethylphenyl)- N-(3,4-dihydroxybenzyl)-2-(1-methyl-1H-pyrazol-4- yl)nicotinamide 483.1695 found, 483.1695 required.2-18

5-(3,5-chloromethylphenyl)- N-[(1-methyl-1H-indol-2-yl)methyl]-2-(1-methyl-1H- pyrazol-4-yl)nicotinamide 470.1731 found,470.1742 required.

Example 3

Methyl 6-chloro-5′-methyl-3,3′-bipyridine-5-carboxylate (3-2)

To a solution of methyl 2-chloro-5-iodonicotonate (3-1, 22 g, 74.0 mmol)in dimethylformamide (296 mL) at 0° C. (ice bath) was added3-methyl-5-pyridylboronic acid (10.13 g, 74.0 mmol), PdCl₂dppf (5.41 g,7.40 mmol) followed by cesium carbonate (84 g, 259 mmol) and water(13.32 mL, 740 mmol) and the system was stirred overnight as the icebath warmed to room temperature. The system was partitioned betweenwater and EtOAc, extracted 3× with EtOAc, combined organics were washedwith brine and dried over magnesium sulfate. Filtration andconcentration yielded a brown oil which upon purification via normalphase chromatography (0→100% EtOAc in Hx) afforded the title compound(3-2) as an off-white solid. ESI+MS [M+H]⁺C₁₃H₁₁ClN₂O₂=262.9.

Methyl 6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxylate (3-3)

To a solution of methyl 6-chloro-5′-methyl-3,3′-bipyridine-5-carboxylate(3-2, 4.25 g, 16.16 mmol) in degassed dimethylformamide (81 mL) at 25°C. was added 2-fluorophenylboronic acid (2.94 g, 21.01 mmol), PdCl₂dppf(1.18 g, 1.62 mmol) and 4M aqueous cesium carbonate (10.1 mL, 40.4mmol). The reaction flask was purged with nitrogen, sealed and stirredfor 4 hours at 40° C. The crude reaction mixture was partitioned betweenwater and EtOAc, separating layers and washing the organic layer withsaturated sodium bicarbonate solution and brine. The solvent was removedby rotary evaporation and the crude product was taken up in DCM (40 mL).Quadrapure TU (6 g) was added and the mixture was stirred overnight atroom temperature. Filtration and concentration afforded the titlecompound (3-3) as a solid. ESI+MS [M+H]⁺C₁₉H₁₅FN₂O₂=323.1.

6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxylic acidhydrochloride (3-4)

To a solution of methyl6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxylate (3-3, 5.57 g,17.28 mmol) in THF/water (84 mL; 5:1) was added 10M sodium hydroxidesolution (3.46 mL, 34.6 mmol) and the reaction was stirred at 60° C.overnight. The reaction mixture was diluted with water, filtered andconcentrated. The crude product was taken up in DMF/DMSO/CH₃CN/water (72mL; 2:2:1:0.5), filtered and purified by reverse phase preparativechromatography (5-40% acetonitrile in water with 0.1% TFA buffer). Theclean fractions were pooled and evaporated to give the TFA salt as awhite solid. This material was taken up in a minimal amount ofTHF/acetonitrile and ethyl ether saturated with HCl was added, forming awhite precipitate. The solvent was decanted away after centrifugation ofthe suspension. This was repeated 2 more times, once with HCl/ether andthen with diethyl ether. After the final decant, the solids were driedunder high vacuum to afford the title compound (3-4) as the HCl salt.ESI+MS [M+H]⁺C₁₈H₁₃FN₂O₂.HCl=309.1.

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxamide(3-5)

To a solution of6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxylic acidhydrochloride (3-4, 3.0 g, 8.70 mmol) in dimethylformamide (43 mL)cooled to 0° C., was added EDC (2.67 g, 13.92 mmol) and HOBt (2.13 g,13.92 mmol) followed by 1-(5,6-dimethoxypyridin-2-yl)methanamine (11-6,1.90 g, 11.31 mmol) and N-methylmorpholine (5.74 mL, 52.2 mmol). Thereaction was allowed to warm to room temperature and stir overnight. Thereaction mixture was partitioned between ethyl acetate and saturatedsodium bicarbonate. The organics were washed with water and brine, thenstripped to dryness. The crude product was taken up in DMF/DMSO (30 mL,1:1), filtered and purified via reverse phase chromatography (5→65%acetonitrile in water with 0.1% TFA buffer). The clean fractions werepooled, partitioned between ethyl acetate and 2M sodium carbonate. Theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated to afford the title compound(3-5) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.99 (d, J=2.5 Hz,1H), 8.74 (d, J=2 Hz, 1H) 8.53 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.77 (s,1H), 7.66 (m, 1H), 7.31 (m, 1H), 7.21 (t, J=14.6 Hz, 1H), 6.98 (d, J=7.8Hz, 1H), 6.92 (t, J=18.3 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.46 (m, 1H),4.44 (d, J=5 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 2.45 (s, 3H). HRMS[M+H] C₂₆H₂₃FN₄O₃ calc'd 459.1827. Found 459.1830.

Example 3A

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(3-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxamide(3-7)

To a solution of6-(3-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxylic acidhydrochloride (3-6, prepared by the method described above for thepreparation of 3-4, 2.5 g, 7.25 mmol) in dimethylformamide (36 mL)cooled to 0° C., was added EDC (1.95 g, 10.2 mmol) and HOBt (1.67 g,10.9 mmol) followed by 1-(5,6-dimethoxypyridin-2-yl)methanamine (11-6,1.46 g, 8.7 mmol) and N-methylmorpholine (4.78 mL, 43.5 mmol). Thereaction stirred for 15 minutes and then was allowed to warm to roomtemperature. After 3.5 hours the reaction mixture was partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organicswere washed with water and brine, dried over Na₂SO₄/MgSO₄, filtered andstripped to dryness. The crude product was recrystallized fromchloroform/ethyl ether to afford the title compound (3-7) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 8.96 (d, J=2.2 Hz, 1H), 8.72 (d, J=1.7Hz, 1H), 8.56 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 7.76 (s, 1H), 7.44 (d,J=7.8 Hz, 1H), 7.40 (d, J=9.5 Hz, 1H), 7.24 (m, 1H), 6.99 (m, 2H), 6.74(d, J=7.8 Hz, 1H), 6.33 (m, 1H), 4.44 (d, J=5.4 Hz, 2H), 3.88 (s, 3H),3.76 (s, 3H), 2.45 (s, 3H). HRMS [M+H] C₂₆H₂₃FN₄O₃ calc'd 459.1827.Found 459.1832.

TABLE 3 The following compounds were prepared using the foregoingmethodology, but substituting the appropriately substituted reagent, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis without undue experimentation. Cmp Structure Name HRMS m/z(M + H) 3-8 

6-(3-chlorophenyl)-N-[(5,6- dimethoxypyridin-2-yl)methyl]-5′-methyl-3,3′- bipyridine-5-carboxamide 475.1527 found,475.1531 required. 3-9 

6-(3-chlorophenyl)-N-[(5,6- dimethoxypyridin-3-yl)methyl]-5′-methyl-3,3′- bipyridine-5-carboxamide 475.1537 found,475.1531 required. 3-10

N-[(5,6-dimethoxypyridin-2- yl)methyl]-5′-methyl-6-phenyl-3,3′-bipyridine-5- carboxamide 441.1904 found, 441.1921 required.3-11

N-(3-chloro-4- methoxybenzyl)-5′-methyl-6- phenyl-3,3′-bipyridine-5-carboxamide 444.1486 found, 444.1473 required. 3-12

N-[(5,6-dimethoxypyrazin-2- yl)methyl]-6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5- carboxamide 460.1792 found, 460.1779required. 3-13

N-(3-chloro-4- methoxybenzyl)-5′-methyl-6- (3-methylphenyl)-3,3′-bipyridine-5-carboxamide 458.1634 found, 458.1630 required. 3-14

6-(2,3-difluorophenyl)-N- [(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-3,3′- bipyridine-5-carboxamide 477.1726 found,477.1733 required. 3-15

5′-chloro-N-[(5,6- dimethoxypyridin-2- yl)methyl]-6-phenyl-3,3′-bipyridine-5-carboxamide 461.1373 found, 461.1375 required. 3-16

N-[(6-cyclopropyl-5- methoxypyridin-2-yl)methyl]-6-(3-fluorophenyl)-5′-methyl- 3,3′-bipyridine-5-carboxamide 469.2021found, 469.2034 required. 3-17

6-(3,5-difluorophenyl)-N- [(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-3,3′- bipyridine-5-carboxamide 477.1747 found,477.1733 required. 3-18

6-(3(5-difluorophenyl)-N- [(5,6-dimethoxypyrazin-2-yl)methyl]-5′-methyl-3,3′- bipyridine-5-carboxamide 478.1700 found,478.1685 required. 3-19

6-(3-chloro-5-fluorophenyl)- N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-3,3′- bipyridine-5-carboxamide 493.1451 found,493.1437 required. 3-20

6-(3-cyanophenyl)-N-[(5,6- dimethoxypyridin-2-yl)methyl]-5′-methyl-3,3′- bipyridine-5-carboxamide 466.1875 found,466.1874 required.

Example 4

5-(3-chloro-5-methylphenyl)-2-morpholin-4-ylnicotinic acid (4-2)

To a solution of methyl 2-chloro-5-iodonicotonate (4-1, 9.34 g, 31.5mmol) in dimethylformamide (157 mL) at 25° C. was added3-chloro-5-methylboronic acid (5.35 g, 31.4 mmol), PdCl₂dppf (2.3 g,3.14 mmol) followed by cesium carbonate (41.0 g, 126 mmol) and water(10.0 mL, 565 mmol) and the system was stirred for 4 h at 25° C. Thesystem was partitioned between water and EtOAc, and dried over magnesiumsulfate. Filtration and concentration yielded a brown solid which uponpurification via normal phase chromatography (0→15% EtOAc in Hx)afforded a white solid. To this white solid (4.0 g, 13.5 mmol) indioxane (67.5 mL) at 25° C. was added morpholine (5.88 g, 67.5 mmol) andthe system was heated to 90° C. for 3 h. The solvent was removed invacuo and the resulting residue was partitioned between water and EtOAcfollowed by purification via normal phase chromatography (5→15% EtOAc inHx) to yield a white foam. To this white foam (4.2 g, 12.11 mmol) in THF(30 mL) and MeOH (30 mL) was added KOH (5.19 mL, 36.3 mmol) and stirredat ambient temperature overnight. The system was then acidified using 6N HCl to a pH of 2.0 and the solvents were azeotroped off with tolueneto afford the title compound (4-2) as a yellow powder. HRMS [M+H]C₁₇H₁₂ClN₂O₃ calc'd 333.1002. Found 333.1000.

5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-(morpholin-4-yl)nicotinamide(4-3)

To a solution of 5-(3-chloro-5-methylphenyl)-2-morpholin-4-ylnicotinicacid (4-2, 2.8 g, 8.41 mmol) and 3,4-dimethoxybenzylamine (6.30 mL, 42.1mmol) in DCM (42 mL) was added EDC (4.84 g, 25.2 mmol), HOBt (3.87 g,25.2 mmol) followed by N-methylmorpholine (9.25 mL, 84 mmol) and thesystem was stirred at 25° C. overnight. The reaction mixture waspartitioned between ethyl acetate and water, washed with saturatedsodium bicarbonate and dried over magnesium sulfate. The reactionmixture was filtered, concentrated and triturated with diethylether toafford the title compound (4-3) as a bone powder. ¹H NMR (400 MHz,CDCl₃) δ 8.82 (m, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H),7.35 (s, 1H), 7.16 (s, 1H), 6.90 (m, 2H), 6.84 (m, 1H), 4.56 (d, J=5.6Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.55 (m, 4H), 3.12 (m, 4H), 2.37(s, 3H). HRMS [M+H] C₂₆H₂₈ClN₃O₄ calc'd 482.1841. Found 482.1847.

TABLE 4 The following compounds were prepared using the foregoingmethodology, but substituting the appropriately substituted reagent, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis without undue experimentation. Cmp Structure Name HRMS m/z(M + H) 4-4 

5-(3-chloro-5-methylphenyl)- N-(3,4-dimethoxybenzyl)-2-piperidin-1-ylnicotinamide 480.2068 found, 480.2048 required. 4-5 

5-(3-chloro-5-methylphenyl)- N-(3,4-dimethoxybenzyl)-2-pyrrolidin-1-ylnicotinamide 466.1896 found, 466.1892 required. 4-6 

2-azetidin-1-yl-5-(3-chloro-5- methylphenyl)-N-(3,4- dimethoxybenzyl)-nicotinamide 452.1726 found, 452.1735 required. 4-7 

5-(3,5-dichlorophenyl)-N- (3,4-dimethoxybenzyl)-2-(3- methoxyazetidin-1-yl)nicotinamide 502.1300 found, 502.1295 required. 4-8 

5-(3,5-dichlorophenyl)-N- (3,4-dimethoxybenzyl)-2-(3- fluoroazetidin-1-yl)nicotinamide 490.1103 found, 490.1095 required. 4-9 

5-(3-chloro-5-methylphenyl)- N-(3,4-dimethoxybenzyl)-2-[(3R)-3-fluoropyrrolidin-1- yl]nicotinamide 484.1805 found, 484.1798required. 4-10

5-(3-chloro-5-methylphenyl)- N-(3,4-dimethoxybenzyl)-2- thiomorpholin-4-ylnicotinamide 498.1622 found, 498.1613 required. 4-11

5-(3,5-dichlorophenyl)-N- [(5,6-dimethoxypyridin-2-yl)methyl]-2-morpholin-4- ylnicotinamide 503.1248 found, 503.1247required. 4-12

5′-chloro-N-[(5,6- dimethoxypyridin-2- yl)methyl]-6-morpholin-4-yl-3,3′-bipyridine-5-carboxamide 470.1608 found, 470.1590 required. 4-13

N-[(5,6-dimethoxypyridin-2- yl)methyl]-5′-methyl-6- morpholin-4-yl-3,3′-bipyridine-5-carboxamide 450.2150 found, 450.2136 required. 4-14

5-(3-chloro-5-methylphenyl)- N-[(5,6-dimethoxypyrazin-2-yl)methyl]-2-morpholin-4- ylnicotinamide 484.1765 found, 484.1746required. 4-15

N-[4-methoxy-3- (trifluoromethyl)benzyl]-5′-methyl-6-pyrrolidin-1-yl-3,3′- bipyridine-5-carboxamide 471.2014 found,471.2002 required. 4-16

N-(3-chloro-4- methoxybenzyl)-5′-methyl-6- pyrrolidin-1-yl-3,3′-bipyridine-5-carboxamide 437.1746 found, 437.1739 required.

Example 5

5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxylic acid(5-2)

To a solution of methyl 2-chloro-5-iodonicotonate (5-1, 10.85 g, 36.5mmol) in dimethylformamide (150 mL) at 25° C. was added3-methyl-5-pyridylboronic acid (5.0 g, 36.5 mmol), PdCl₂dppf (2.67 g,3.65 mmol) followed by cesium carbonate (41.6 g, 128 mmol) and water(6.57 mL, 365 mmol) and the system was stirred for 4 h at 25° C. Thesystem was partitioned between water and EtOAc, and dried over magnesiumsulfate. Filtration and concentration yielded a brown oil which uponpurification via normal phase chromatography (0→100% EtOAc in Hx)afforded a brown semi-solid which was then tritirated with MeOH anddiethylether to yield a dark tan powder. To this tan powder (0.5 g, 1.9mmol) in dioxane (13 mL) was added 3-methylpyrazole (0.47 g, 5.7 mmol)and NaHMDS (1.9 mL, 3.81 mmol) and the system was heated to 125° C. for20 minutes in the microwave reactor. The reaction contents werepartitioned between water and EtOAc followed by purification via normalphase chromatography (20→100% EtOAc in Hx) to yield a clear oil. To thisclear oil (0.31 g, 1.0 mmol) in THF (2.5 mL) and MeOH (2.5 mL) was addedKOH (2.0 mL, 2.0 mmol) and stirred at 135° C. for 10 minutes in amicrowave reactor. The system was then acidified using 6 N HCl to a pHof 2.0 and the solvents were azeotroped off with toluene to afford thetitle compound (5-2) as a bone powder. ESI+MS [M+H]⁺C₁₆H₁₄N₄O₂=295.1.

5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-N-[(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl]-3,3′-bipyridine-5-carboxamide(5-3)

To a solution of5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxylic acid(5-2, 0.025 g, 0.085 mmol) and1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methanamine (0.015 g, 0.085mmol) in ACN (0.85 mL) was added 1-propylphosphonic acid cyclicanhydride (T3P, 0.15 mL, 0.255 mmol) followed by Hunig's base (0.089 mL,0.51 mmol) and the system was stirred at 40° C. for 1 h in an oil bath.The reaction mixture was cooled and partitioned between EtOAc and water,washed with saturated sodium bicarbonate and dried over magnesiumsulfate. The reaction mixture was filtered, concentrated and purifiedvia normal phase chromatography (0→10% MeOH in EtOAc) to afford thetitle compound (5-3) as a bone powder. ¹H NMR (500 MHz, CDCl₃) δ 8.68(m, 1H), 8.51 (m, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 7.72 (m, 1H), 7.12(m, 1H), 7.0 (m, 1H), 6.90 (m, 1H), 6.54 (m, 1H), 6.27 (m, 1H), 4.46 (m,2H), 3.22 (m, 2H), 2.88 (s, 3H), 2.74 (m, 2H), 2.44 (s, 3H), 2.28 (s,3H), 1.97 (m, 2H). HRMS [M+H] C₂₇H₂₈N₆O calc'd 453.2391. Found 453.2397.

TABLE 5 The following compounds were prepared using the foregoingmethodology, but substituting the appropriately substituted reagent, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis without undue experimentation. Cmp Structure Name HRMS m/z(M + H) 5-4

N-[(5,6-dimethoxypyridin-2- yl)methyl]-5-(3,5-dimethylphenyl)-2-(4-methyl- 1H-pyrazol-1-yl)nicotinamide 458.2208found, 458.2187 required. 5-5

5-(3-chloro-5-fluorophenyl)- N-[(5,6-dimethoxypyridin-2-yl)methyl]-2-(4-methyl-1H- pyrazol-1-yl)nicotinamide 482.1407 found,482.1390 required. 5-6

N-(3-cyclopropyl-4- methoxybenzyl)-5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)- 3,3′-bipyridine-5-carboxamide 454.2232found, 454.2238 required. 5-7

N-(3-chloro-4- methoxybenzyl)-5-(3-fluoro- 5-methoxyphenyl)-2-(1H-pyrazol-1-yl)nicotinamide 467.1278 found, 467.1281 required. 5-8

N-(3-chloro-4- methoxybenzyl)-5′-methyl-6- (1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxamide 434.1382 found, 434.1378 required. 5-9

N-[(5,6-dimethoxypyridin-2- yl)methyl]-5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′- bipyridine-5-carboxamide 445.1977 found,445.1983 required.  5-10

N-(3-ethyl-4-methoxybenzyl)- 5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine- 5-carboxamide 442.2233 found, 442.2238required.  5-11

N-(3-chloro-4- methoxybenzyl)-5′-methyl-6- (3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxamide 448.1544 found, 448.1535 required.  5-12

5-(3-chloro-5-methylphenyl)- N-(3,4-dimethoxybenzyl)-2-(4-methyl-1H-pyrazol-1- yl)nicotinamide 477.1710 found, 477.1688required.

Example 6

Methyl 6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxylate (6-2)

To a solution of methyl 6-chloro-5′-methyl-3,3′-bipyridine-5-carboxylate(6-1, 0.15 g, 0.57 mmol, 1.0 equiv, prepared in an analogous fashion toExamples 2 and 8) in dioxane (2.9 mL) at 25° C. was addedcyclopentylzinc bromide (3.43 mL, 1.71 mmol, 3.0 equiv, 0.5 M in THF)and tetrakis(triphenylphosphine)palladium(0) (0.099 g, 0.086 mmol, 0.15equiv). The reaction mixture was heated for 3 h at 90° C. The reactionmixture was cooled partitioned between water (10 mL) and EtOAc (30 mL),washed with water (3×30 mL) and brine (1×30 mL), and the organic phasewas dried over magnesium sulfate. The residue was purified via normalphase chromatography (5 to 100% EtOAc in hexanes, silica) to afford thedesired product (6-2) as an oil after concentration. ESI+MS [M+H]⁺C₁₈H₂₀N₂O₂ calc'd 297.2. Found 297.1.

Sodium 6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxylate (6-3)

To a solution of methyl6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxylate (6-2, 0.060 g,0.020 mmol, 1.0 equiv) in THF/methanol (1.7 mL/0.3 mL) was added 10 Nsodium hydroxide (0.10 mL, 1.0 mmol, 5.0 equiv) and the system wasstirred for 18 h at ambient temperature. The reaction mixture wasconcentrated and azeotroped with ethyl acetate (2×10 mL) and toluene(3×10 mL) to afford the desired product (6-3) as a white solid. ESI+MS[M+H]⁺C₁₇H₁₈N₂O₂ calc'd 283.1. Found 283.0.

6-cyclopentyl-N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-3,3′-bipyridine-5-carboxamide(6-4)

To a suspension of sodium6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxylate (6-3, 0.022 g,0.078 mmol, 1.0 equiv) in acetonitrile (0.8 mL) was added1-(5,6-dimethoxypyridin-2-yl)methanamine (11-6, 0.039 g, 0.234 mmol, 3.0equiv), 1-propylphosphonic acid cyclic anhydride (0.149 g, 0.234 mmol,3.0 equiv, 50 weight percent in EtOAc), and diisopropylethylamine (0.060g, 0.47 mmol, 6.0 equiv) and the system was heated to 40° C. for 24 h.The reaction mixture was cooled and diluted with ethyl acetate (30 mL).The reaction mixture was washed with saturated sodium bicarbonate (2×10mL), water (2×10 mL) and brine (1×10 mL), dried over magnesium sulfateand concentrated. The residue was purified via normal phasechromatography (0 to 40% methanol in EtOAc, silica) followed by reversephase chromatography (5 to 65% acetonitrile in water, 0.1% TFA buffer)to afford the desired product (6-4) as a white solid after free-basingand concentration. ¹H NMR (500 MHz, CDCl₃) δ 8.83 (d, J=2.5 Hz, 1H),8.62 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.65 (s,1H), 7.05 (d, J=8.0 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.72 (bs, 1H), 4.64(d, J=5.0 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.52-3.48 (m, 1H), 2.42(s, 3H), 2.04-1.80 (m, 6H), 1.70-1.60 (m, 2H). HRMS [M+H] C₂₅H₂₈N₄O₃calc'd 433.2234. Found 433.2226.

TABLE 6 The following compounds were prepared using the foregoingmethodology, but substituting the appropriately substituted reagent, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis without undue experimentation. Cmp Structure Name HRMS m/z (M+H) 6-5

6-cyclopentyl-N-(3,4- dimethoxybenzyl)-5′-methyl-3,3′-bipyridine-5-carboxamide 432.2287 found, 432.2282 required. 6-6

N-(3-chloro-4- methoxybenzyl)-6- cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxamide 436.1794 found, 436.1786 required. 6-7

6-cyclopentyl-N-[4-methoxy- 3-(trifluoromethyl)benzyl]-5′-methyl-3,3′-bipyridine-5- carboxamide 470.2044 found, 470.2050 required.

Example 7

5-bromo-2,3-dimethoxypyridine (7-2)

To a solution of 2,3-dimethoxypyridine (7-1, 2.5 g, 18.0 mmol, 1.0equiv) in dichloromethane:saturated NaHCO₃ (80 mL: 40 mL) at 0° C. wasadded bromine (0.93 mL, 18.0 mmol, 1.0 equiv) and the reaction mixturewas stirred for 2 h at 25° C. The reaction mixture was quenched withsolid Na₂SO₃ (˜10 g) and the aqueous phase was extracted withdichloromethane (3×100 mL). The organic phase was dried over magnesiumsulfate and concentrated. The residue was purified via normal phasechromatography (0 to 20% EtOAc in hexanes, silica) to afford the desiredproduct (7-2) as an oil after concentration. ESI+MS [M+H]⁺C₇H₈NO₂ calc'd218.0. Found 218.0.

5,6-dimethoxynicotinonitrile (7-3)

To a solution of 5-bromo-2,3-dimethoxypyridine (7-2, 0.300 g, 1.38 mmol,1.0 equiv) in dimethylformamide (3.9 mL) was added copper (I) cyanide(0.15 g, 1.65 mmol, 1.2 equiv) and the reaction mixture was heated for40 minutes at 180° C. in a microwave reactor. The reaction mixture wascooled and partitioned between EtOAc (50 mL) and water (50 mL). Theorganic phase was washed with water (2×30 mL) and brine (1×30 mL), driedover magnesium sulfate and concentrated. The residue was purified vianormal phase chromatography (0 to 40% EtOAc in hexanes, silica) toafford the desired product (7-3) as white solid after concentration.ESI+MS [M+H]⁺C₈H₈N₂O₂ calc'd 165.1. Found 165.1.

1-(5,6-dimethoxypyridin-3-yl)methanamine (7-4)

To a solution of 5,6-dimethoxynicotinonitrile (7-3, 0.600 g, 3.65 mmol,1.0 equiv) in methanol (20 mL) under a nitrogen atmosphere was addedPearlman's catalyst (0.205 g, 0.292 mmol, 0.08 equiv, 20 weight percent)and concentrated HCl (2.44 mL), and the reaction was place under anatmosphere of hydrogen. After 2 h, the reaction was placed under anatmosphere of nitrogen and filtered through celite to remove thecatalyst. The reaction mixture was dissolved in EtOAc, dried over MgSO₄and concentrated to an oily solid (7-4) of high purity. ESI+MS [M+H]⁺C₈H₁₂N₂O₂ calc'd 169.1. Found 169.1.

Example 8

3-cyclopropyl-4-methoxybenzonitrile (8-2)

A mixture of 3-bromo-4-methoxybenzonitrile (8-1, 5.0 g, 23.6 mmol, 1.0eq), aqueous potassium phosphate tribasic (65.0 ml, 1.27 M, 3.5 eq),cyclopropylboronic acid (10.1 g, 118 mmol, 5.0 eq), Pd(OAc)₂ (0.539 g,2.36 mmol, 0.1 eq) and tricyclohexylphosphine (0.661 g, 2.36 mmol, 0.1eq) was stirred in degassed toluene (103 ml) and heated to 80° C. forthree hours. An additional amount of cyclopropylboronic acid (1.0 g,1.16 mmol, 0.5 eq) was added and the solution was further heated for 16hours at 80° C. to complete the reaction. The reaction mixture wascooled and partitioned between brine and EtOAc. The organic phase wasdried over sodium sulfate, filtered and concentrated to give an orangeoil. The oil was purified by normal phase column chromatography (0 to10% EtOAc in hexanes) to afford the product (8-2) as a yellow oil. ¹HNMR (CDCl₃) δ 7.44 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz), 6.86(d, 1H, J=8.4 Hz), 3.92 (s, 3H), 2.13 (m, 1H), 0.97 (m, 2H), 0.65 (m,2H).

1-(3-cyclopropyl-4-methoxyphenyl)methanamine (8-3)

Lithium aluminum hydride in diethyl ether (17.3 ml, 1.0 M, 17.3 mmol,3.0 eq) was carefully added over twenty minutes to a solution of3-cyclopropyl-4-methoxybenzonitrile (8-2, 1.0 g, 5.77 mmol, 1.0 eq) intetrahydrofuran (28.9 ml) at 0° C. under nitrogen atmosphere. Theresulting dark orange mixture was allowed to stir at 0° C. for 30 min,then carefully quenched in the following order: water (1.0 ml), 15% NaOHaqueous (1.0 ml) and water (3.0 ml). The resulting emulsion was stirredat room temperature for 30 min. Several spatula amounts of magnesiumsulfate was added to the mixture to remove any water. The entire mixturewas filtered through a pad of sodium sulfate, washing with ethylacetate. The collected filtrate was concentrated to give the product(8-3) as a yellow oil. ESI+MS [M−16]⁺C₁₁H₁₅NO: 161.1 found, 161.2required.

Example 9

6-Bromo-5-methoxypyridine-2-carbonitrile (9-2)

To a solution of 2-bromo-6-iodo-3-methoxypyridine (9-1 or 11-3, 2.1 g,6.69 mmol, 1.0 equiv) in dichloromethane (17 mL) was addedisopropylmagnesium chloride (2.0 M, 4.35 mL, 8.70 mmol, 1.3 equiv)slowly at 0° C. and the reaction mixture was stirred for 45 minutes. Thereaction mixture was then cooled to −78° C. and a solution oftoluenesulfonyl cyanide (1.8 g, 10.03 mmol, 1.5 equiv) indichloromethane (5 mL) was added slowly. The reaction mixture wasallowed to warm to ambient temperature over 4 hours. To quench, 2 N HClwas added until neutral pH was obtained. The reaction mixture waspartitioned between water and dichloromethane and the aqueous phase wasextracted with dichloromethane (3×50 mL). The combined organic layer wasdried over MgSO₄, concentrated and the residue was purified by normalphase column chromatography (10-50% EtOAc in hexanes) to afford theproduct (9-2) as a tan solid. ESI+MS [M+H]⁺C₇H₆BrN₂O: 212.9 found, 213.0required.

5-Methoxy-6-vinylpyridine-2-carbonitrile (9-3)

In a microwave vial, 6-bromo-5-methoxypyridine-2-carbonitrile (9-2, 200mg, 0.94 mmol, 1.0 equiv), potassium trifluoro(vinyl)borate (314 mg,2.35 mmol, 2.5 equiv), tricyclohexylphosphine (52.7 mg, 0.19 mmol, 0.2equiv), palladium(II) acetate (21.1 mg, 0.09 mmol, 0.1 equiv), andtripotassium phosphate (697 mg, 3.29 mmol, 3.5 equiv) were suspended intoluene (10 mL) and water (0.5 mL). The reaction mixture was heated in amicrowave reactor for 20 minutes at 130° C. and then filtered, rinsingwith EtOAc. The filtrate was concentrated and the residue purified bynormal phase column chromatography (10-35% EtOAc in hexanes) to affordthe product (9-3). ESI+MS [M+H]⁺C₉H₉N₂O: 161.0 found, 161.1 required.

1-(6-Ethyl-5-methoxypyridin-2-yl)methanamine dihydrochloride (9-4)

To a suspension of 5-methoxy-6-vinylpyridine-2-carbonitrile (9-3, 88 mg,0.55 mmol, 1 equiv) in methanol (3 mL) was added palladium hydroxide oncarbon (19.29 mg, 0.03 mmol, 0.05 equiv) and concentrated HCl (360 uL,4.40 mmol, 8 equiv) and the reaction mixture stirred under an atmosphereof hydrogen overnight. The reaction mixture was filtered over celite,rinsing with methanol, and concentrated to give desired product (9-4) asthe dihydrochloride salt. ESI+MS [M+H]⁺C₉H₁₅N₂O: 167.0 found, 167.2required.

6-Cyclopropyl-5-methoxypyridine-2-carbonitrile (9-5)

In a microwave vial, 6-bromo-5-methoxypyridine-2-carbonitrile (9-2, 300mg, 1.41 mmol, 1.0 equiv), potassium cyclopropyl(trifluoro)borate (521mg, 3.52 mmol, 2.5 equiv), tricyclohexylphosphine (158 mg, 0.56 mmol,0.4 equiv), palladium(II) acetate (63.2 mg, 0.28 mmol, 0.2 equiv) andtripotassium phosphate (1046 mg, 4.93 mmol, 3.5 equiv) were suspended intoluene (15 mL) and water (0.75 mL). The reaction mixture was heated ina microwave reactor for 60 minutes at 130° C. and then filtered, rinsingwith EtOAc. The filtrate was concentrated and the residue purified bynormal phase column chromatography (10-35% EtOAc in hexanes) to affordthe product (9-5). ESI+MS [M+H]⁺C₁₀H₁₁N₂O: 175.1 found, 175.2 required.

1-(6-cyclopropyl-5-methoxypyridin-2-yl)methanamine (9-6)

To a solution of 6-cyclopropyl-5-methoxypyridine-2-carbonitrile (9-5,115 mg, 0.66 mmol, 1 equiv) in THF (2.6 mL) at 0° C. was added LAH (1 M,1.98 mL, 1.98 mmol, 3 equiv) slowly. The reaction mixture was stirredand allowed to warm to ambient temperature over 3 hours. The reactionmixture was then diluted with EtOAc (2 mL), and water (50 uL), NaOH(aq., 20 wt. %, 50 uL) and water (100 uL) were added sequentially. Thereaction mixture was then dried over MgSO₄, filtered and concentrated toafford the product (9-6). ESI+MS [M+H]⁺C₁₀H₁₅N₂O: 179.1 found, 179.2required.

Example 10

3,4-Bis(difluoromethoxy)benzaldehyde (10-2)

In a sealed tube 3,4-dihydroxybenzaldehyde (10-1, 750 mg, 5.43 mmol, 1.0equiv), sodium chlorodifluoroacetate (3310 mg, 21.7 mmol, 4 equiv), andpotassium carbonate (1800 mg, 13.03 mmol, 2.4 equiv) were suspended inDMF (24.4 mL) and water (2.7 mL). The reaction mixture was stirred at100° C. for 4 hours and was cooled to ambient temperature. HCl (6 N, 10mL) and water (30 mL) were added and the reaction stirred for anadditional 2 hours. NaOH (5 N, aq.) was added until a pH of 10 wasobtained. The mixture was extracted with MTBE (3×, 50 mL), dried overMgSO₄ and concentrated to afford the desired product (10-2). ¹H NMR(CDCl₃, 400 MHz) δ 9.97 (s, 1H), 7.76-7.79 (m, 2H), 7.43 (d, J=8.1 Hz,1H), 6.64 (t, J=73.8 Hz, 1H), 6.60 (t, J=73.8 Hz, 1H).

1-[3,4-Bis(difluoromethoxy)phenyl]methanamine hydrochloride (10-3)

To a solution of 3,4-bis(difluoromethoxy)benzaldehyde (10-2, 100 mg,0.42 mmol, 1 equiv) in THF (840 uL) was added2-methylpropane-2-sulfinamide (56 mg, 0.46 mmol, 1.1 equiv) and titaniumethoxide (440 uL, 2.10 mmol, 5.0 equiv), and the reaction mixturestirred at ambient temperature for 4.5 hours. The reaction mixture wasthen cooled to 0° C. and sodium borohydride (31.8 mg, 0.84 mmol, 2.0equiv) was added portionwise and the reaction was stirred for anadditional hour. Methanol (2 mL) was added slowly and the reactionmixture was partitioned between EtOAc (20 mL) and brine (20 mL) andfiltered. The organic phase was dried over MgSO₄ and concentrated toafford crudeN-[3,4-bis(difluoromethoxy)benzyl]-2-methylpropane-2-sulfinamide, whichwas dissolved in methanol (2.2 mL). To the solution was added HCl (2 Min ether, 655 uL, 3 equiv), and the reaction mixture stirred for 30minutes. It was then concentrated to afford the desired product (10-3)as a white solid. ESI+MS [M−NH₂]⁺ C₉H₇F₄O₂: 223.0 found, 223.0 required.

Example 11

2-bromo-3-hydroxy-6-iodopyridine (11-2)

To a solution of 2-bromo-3-hydroxypyridine (11-1, 28 g, 161 mmol) inwater (360 mL) was added K₂CO₃ (22.24 g, 161 mmol) and I₂ (20.42 g, 80mmol). The system was stirred for 1.5 h at ambient temperature, cooledto 0° C. and then treated with concentrated HCl until solidsprecipitated from solution (pH˜6.0). The solids were isolated byfiltration and dried to give the title compound (11-2) as a brown solid.ESI+MS C₅H₃BrINO: 299.8 found, 299.9 required.

2-bromo-3-methoxy-6-iodopyridine (11-3)

To a solution of 2-bromo-3-hydroxy-6-iodopyridine (11-2, 40 g, 133 mmol)in DMF (80 ml) was added K₂CO₃ (16.77 g, 121 mmol) and methyl iodide(66.3 g, 467 mmol). The system was stirred for 45 minutes at 100° C.,cooled to room temperature and then treated with water (650 mL) andstirred for 0.5 h. The resulting solids that precipitated from solutionwere isolated by filtration and dried to give the title compound (11-3)as a pale brown solid. ESI+MS C₆H₅BrINO: 313.8 found, 313.9 required.

2,3-dimethoxy-6-iodopyridine (11-4)

To a solution of 2-bromo-3-methoxy-6-iodopyridine (11-3, 34 g, 162 mmol)in DMF (65 mL) was added sodium methoxide (37 mL, 162 mmol) and heatedto 100° C. The mixture was stirred for 10 minutes and partitionedbetween saturated NaHCO₃ and DCM. The organic phase was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude materialwas purified by gradient elution on silica (0 to 20% EtOAc in hexanes)to afford the title compound (11-4) as a white powder. ESI+MS[M+H]⁺C₇H₈INO₂: 265.8 found, 266.0 required.

2,3-dimethoxy-6-cyanopyridine (11-5)

To a solution of 2,3-dimethoxy-6-iodopyridine (11-4, 24.0 g, 91 mmol) inDMF (181 mL) was added copper cyanide (9.73 g, 109 mmol) and heated to150° C. for 20 minutes in a microwave reactor. The mixture waspartitioned between water and EtOAc. The organic phase was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude materialwas purified by gradient elution on silica gel (0 to 40% EtOAc inhexanes) to yield the desired product (11-5) as an off-white crystallinepowder. ESI+MS [M+H]⁺C₈H₈N₂O₂: 165.0 found, 165.1 required.

2,3-dimethoxy-6-aminomethylpyridine (11-6)

To a solution of 2,3-dimethoxy-6-cyanopyridine (11-5, 5.1 g, 31.1 mmol)in MeOH (260 mL) was added Pearlman's catalyst (2.18 g, 3.11 mmol) andconcentrated HCl (20.0 mL, 249 mmol). The system was then stirred underan atmosphere of hydrogen via a balloon for 1.5 h. The reaction contentswere filtered through a pad of celite and methanol was removed in vacuo.The crude mixture was then basified using saturated Na₂CO₃ and thenextracted using 4:1 Chloroform:Ethanol. The organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated to yield thedesired product (11-6) as a bone semi-solid. ESI+MS [M+H]⁺ C₈H₁₂N₂O₂:M−16 (—NH₂), 152.06 found, 152.2 required.

Example 12

3-ethyl-4-methoxybenzonitrile (12-2)

To a solution of 3-bromo-4-methoxybenzonitrile (12-1, 0.3 g, 1.42 mmol)in DMF (14 mL) was added tetraethyltin (0.56 mL, 2.83 mmol),bis(tri-t-butylphosphine) palladium(0) (0.072 g, 0.141 mmol), andlithium chloride (0.18 g, 4.24 mmol) and the system was heated to 135°C. for 30 minutes in a microwave reactor. The mixture was partitionedbetween saturated NaHCO₃ and EtOAc. The organic phase was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude materialwas purified by gradient elution on silica gel (0 to 10% EtOAc inhexanes) to yield the desired product (12-2) as a clear oil. ESI+MS[M+H]⁺C₁₀H₁₁NO: 162.1 found, 162.2 required.

3-ethyl-4-methoxybenzylamine (12-3)

To a solution of 3-ethyl-4-methoxybenzonitrile (12-2, 0.12 g, 0.71 mmol)in MeOH (3.5 mL) was added Pearlman's catalyst (0.020 g, 0.036 mmol) andconcentrated HCl (0.47 mL, 5.71 mmol). The system was then stirred underan atmosphere of hydrogen via a balloon overnight. The reaction contentswere filtered through a pad of celite and solvents were removed in vacuoto yield the desired product (12-3) as a salmon colored crystallinesolid in the form of a mono HCl salt. ESI+MS [M+H]⁺C₈H₁₂N₂O₂: M−16(—NH₂), 149.07 found, 149.2 required.

Example 13

3-methoxy-4-ethyl-benzonitrile (13-2)

To a solution of 3-methoxy-4-hydroxybenzonitrile (13-1, 2.0 g, 13.4mmol) in DCM (67 mL) at −78° C. was added diisopropylethylamine (3.0 mL,17.4 mmol) followed by triflic anhydride (2.7 mL, 16.0 mmol) and stirredat −78° C. for 1 h. The mixture was poured into a separatory funnelcontaining a few pieces of ice and then partitioned between ice waterand ether. The organic phase was washed with 1N HCl and then 10% Na₂CO₃,dried over Na₂SO₄, filtered and concentrated to yield a pale yellow oil.To a solution of this oil (2.7 g, 9.60 mmol) in DMF (96.0 mL) was addedtetraethyl tin (3.80 mL, 19.2 mmol), bis(tri-t-butylphosphine)palladium(0) (0.491 g, 0.960 mmol) and LiCl (1.22 g, 28.8 mmol) and thesystem was heated to 80° C. for 1 h in an oil bath. The mixture waspartitioned between saturated NaHCO₃ and EtOAc. The organic phase waswashed with water, brine, dried over Na₂SO₄, filtered and concentrated.The crude material was purified by gradient elution on silica gel (0 to20% EtOAc in hexanes) to afford the desired compound (13-2) as a paleyellow crystalline solid. ESI+MS [M+H]⁺C₁₀H₁₁NO: 162.1 found, 162.2required.

3-methoxy-4-ethylbenzylamine (13-3)

To a solution of 3-methoxy-4-ethyl-benzonitrile (13-2, 1.5 g, 9.31 mmol)in THF (45 mL) at 0° C. was added LAH (40 mL, 40.0 mmol) and stirred at0° C. for 0.5 h. Quenched carefully over a period of 0.5 h with EtOAc at0° C. and stirred for 15 minutes. Following this, water (1.5 mL) wasadded to this mixture and stirred for 15 minutes followed by 15% NaOH(1.5 mL) and again stirred for 15 minutes. Lastly, water (4.5 mL) wasadded and stirred for 15 more minutes. The mixture was dried overMg₂SO₄, filtered and concentrated to yield a clear semi-solid. Thissemi-solid was treated with 2.0M HCl in ether (4.65 mL, 9.3 mmol) andthe reaction contents were concentrated to afford the desired product asa white powder (13-3) in the form of a mono HCl salt. ESI+MS[M+H]⁺C₈H₁₂N₂O₂: M−16 (—NH₂), 149.1 found, 149.2 required.

Example 14

2,3-dimethoxy-5-aminomethylpyrazine (14-2)

To a solution of 2,3-dichloropyrazine (14-1, 3.5 g, 23.5 mmol) in MeOH(115 mL) was added NaOMe (15.0 mL, 70.5 mmol) and the system was stirredovernight. The reaction contents were then filtered through a frittedfunnel of medium porosity, concentrated, and partitioned between EtOAcand water. The organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated to afford a clear oil. To this clear oil (2.5g, 17.8 mmol) in DMF (17 ml) at 0° C. was added NBS (3.5 g, 19.6 mmol)the system was stirred overnight. The system was quenched with Na₂SO₃and then poured into ice water. The resulting solids that precipitatedfrom solution were isolated by filtration and dried to afford a whitesolid. To this white solid (1 g, 4.5 mmol) in DMF (9 mL) was addedcopper cyanide (0.45 g, 5.0 mmol) and heated to 185° C. for 20 minutesin the microwave reactor. The mixture was cooled and partitioned betweenEtOAc and water. The organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude material was purified bygradient elution on silica (0 to 65% EtOAc in hexanes) to afford a whitepowder. To this white powder (0.740 g, 4.5 mmol) in MeOH (40 mL) wasadded Pearlman's catalyst (0.315 g, 0.45 mmol) and concentrated HCl (3.0mL, 36 mmol). The system was then stirred under an atmosphere ofhydrogen via a balloon for 1.5 h. The reaction contents were filteredthrough a pad of celite followed by removal of methanol in vacuo. Thecrude mixture was then dissolved in DCM, basified using saturated Na₂CO₃and then extracted several times with DCM. The organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated to yield thedesired product (14-2) as a bone solid. ESI+MS [M+H]⁺C₇H₁₁N₃O₂: M−16(—NH₂), 152.8 found, 152.2 required.

Example 15

6-Isopropenyl-5-methoxypyridine-2-carbonitrile (15-2)

In a microwave vial, 6-bromo-5-methoxypyridine-2-carbonitrile (15-1 or9-2, 200 mg, 0.94 mmol, 1.0 equiv), potassiumtrifluoro(isopropenyl)borate (Molander, Gary A., J. Am. Chem. Soc.Commun. 2003, 125, 11148-11149.) (347 mg, 2.35 mmol, 2.5 equiv),tricyclohexylphosphine (52.7 mg, 0.19 mmol, 0.2 equiv), palladium(II)acetate (21.1 mg, 0.09 mmol, 0.1 equiv), and tripotassium phosphate (697mg, 3.29 mmol, 3.5 equiv) were suspended in toluene (10 mL) and water(0.5 mL). The reaction mixture was heated in a microwave reactor for 20minutes at 130° C. and then filtered, rinsing with EtOAc. The filtratewas concentrated and the residue purified by normal phase columnchromatography (15-40% EtOAc in hexanes) to afford the title compound(15-2). ESI+MS [M+H]⁺C₁₀H₁₁N₂O: 175.1 found, 175.2 required.

1-(6-Isopropyl-5-methoxypyridin-2-yl)methanamine dihydrochloride (15-3)

To a suspension of 6-isopropenyl-5-methoxypyridine-2-carbonitrile (15-2,132 mg, 0.76 mmol, 1 equiv) in methanol (4 mL) was added palladiumhydroxide on carbon (26.6 mg, 0.04 mmol, 0.05 equiv) and concentratedHCl (500 uL, 6.06 mmol, 8 equiv) and the reaction mixture stirred underan atmosphere of hydrogen for three hours. The reaction mixture wasfiltered over celite, rinsing with methanol, and concentrated to givethe title compound (15-3) as the dihydrochloride salt. ESI+MS[M+H]⁺C₁₀H₁₇N₂O: 181.1 found, 181.3 required.

Example 16

2-Ethoxy-6-iodo-3-methoxypyridine (16-2)

In a microwave vial, 2-bromo-6-iodo-3-methoxypyridine (16-1 or 131-3,150 mg, 0.48 mmol, 1 equiv) was dissolved in DMF (300 uL). Sodiumethoxide (268 uL, 21 wt % in EtOH, 0.72 mmol, 1.5 equiv) was added tothe solution, and the reaction was heated in the microwave for 5 minutesat 100° C. The reaction mixture was partitioned between saturated NaHCO₃and DCM. The organic phase was washed once with brine, dried over Mg₂SO₄and concentrated. The residue was purified by normal phase columnchromatography (0-20% EtOAc in hexanes) to give the title compound(16-2). ESI+MS [M+H]⁺C₈H₁₁INO₂: 280.0 found, 280.1 required.

6-Ethoxy-5-methoxypyridine-2-carbonitrile (16-3)

To a solution of 2-ethoxy-6-iodo-3-methoxypyridine (16-2, 100 mg, 0.36mmol, 1 equiv) in DMF (675 uL) was added copper cyanide (39 mg, 0.43,mmol, 1.2 equiv). The reaction mixture was heated in a microwave reactorat 150° C. for 20 minutes, and then was partitioned between DCM (50 mL)and water (50 mL). The aqueous layer was extracted with DCM (3×25 mL),and the organic phase was dried over Mg₂SO₄, concentrated and purifiedby normal phase column chromatography (20-50% EtOAc in hexanes) to yieldthe title compound (16-3) as a white solid. ESI+MS [M+H]⁺C₉H₁₁N₂O₂:179.1 found, 179.2 required.

1-(6-Ethoxy-5-methoxypyridin-2-yl)methanamine dihydrochloride (16-4)

To a solution of 6-ethoxy-5-methoxypyridine-2-carbonitrile (16-3, 48 mg,0.27 mmol, 1 equiv) in methanol (1.5 mL) was added 20 weight percentpalladium hydroxide on carbon (9.5 mg, 0.01 mmol, 0.05 equiv) andconcentrated HCl (177 uL, 2.16 mmol, 8 equiv) and the reaction mixturestirred under an atmosphere of hydrogen overnight. The reaction mixturewas filtered over celite, rinsing with methanol, and concentrated togive the title compound (16-4) as the dihydrochloride salt. ESI+MS[M+H]⁺C₉H₁₅N₂O₂: 183.1 found, 183.2 required.

TABLE The following table shows representative data for the compounds ofthe Examples as orexin receptor antagonists as determined by theforegoing assays. Cmpd Structure OX2R K_(i) (nM) 1-13

4.8  1-14

0.07 2-14

0.15 3-5 

0.74 3-7 

0.32 3-15

0.45 4-5 

0.45 4-13

1.1  5-11

0.95 6-5 

2.3 

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1. A compound of the formula I:

wherein: A¹ is selected from the group consisting of phenyl, naphthyland heteroaryl; A² is selected from the group consisting of phenyl,naphthyl and heteroaryl; A³ is selected from the group consisting ofphenyl, naphthyl, C₃₋₆cycloalkyl, and heterocycle, with the provisiothat if A¹ is heteroaryl and A² is heteroaryl, then A³ is other thenphenyl or napthyl; R^(1a), R^(1b) and R^(1c) may be absent if thevalency of A¹ does not permit such substitution and are independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)hydroxyl, (4) —(C═O)_(m)O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1(wherein if m is 0 or n is 0, a bond is present) and where the alkyl isunsubstituted or substituted with one or more substituents selected fromR¹³, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR¹³, (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornaphthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R¹³,(c) C₃₋₆alkenyl, which is unsubstituted or substituted with R¹³, (d)C₃₋₆alkynyl, which is unsubstituted or substituted with R¹³, (e)C₃₋₆cycloalkyl which is unsubstituted or substituted with R¹³, (f)phenyl, which is unsubstituted or substituted with R¹³, and (g)heterocycle, which is unsubstituted or substituted with R¹³, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R^(2a), R^(2b) and R^(2c) may be absent if the valency ofA² does not permit such substitution and are independently selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornaphthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R^(3a), R^(3b) and R^(3c) may be absent if the valency of A³ does notpermit such substitution and are independently selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornaphthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;with the proviso that if A³ is pyridyl, at least one of R^(3a), R^(3b)and R^(3c) is other than hydrogen; R⁴ and R⁵ are independently selectedfrom hydrogen and C₁₋₆alkyl, which is unsubstituted or substituted withone or more substituents selected from R¹³, or R⁴ and R⁵ may be joinedtogether to form a C₃₋₆cycloalkyl with the carbon atom to which they areattached, where the cycloalkyl is unsubstituted or substituted with oneor more substituents selected from R¹³; R⁶ is hydrogen, C₁₋₆alkyl orC₃₋₆cycloalkyl, which is unsubstituted or substituted with one or moresubstituents selected from R¹³; R¹³ is selected from the groupconsisting of: (1) halogen, (2) hydroxyl, (3)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹⁴, (4)—O_(n)—(C₁₋₃)perfluoroalkyl, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, wherethe cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (6) —(C═O)_(m)—C₂₋₄alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹⁴, (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹⁴, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where thephenyl or naphthyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R¹⁴ is selected from the group consisting of: (1) hydroxyl, (2) halogen,(3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6)—O(C═O)—C₁₋₆alkyl, (7) —NH—C₁₋₆alkyl, (8) phenyl, (9) heterocycle, (10)—CO₂H, and (11) —CN; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1 wherein A¹ is phenyl.
 3. The compound of claim 1wherein A¹ is pyridyl.
 4. The compound of claim 1 wherein A² is phenyl.5. The compound of claim 1 wherein A² is heteroaryl.
 6. The compound ofclaim 1 wherein A³ is phenyl.
 7. The compound of claim 1 wherein R^(1a),R^(1b) and R^(1c) are independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl, phenyl or napthyl,(5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl, (6) heteroaryl, wherein heteroaryl is selected frompyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl, which isunsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, (7) phenyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, and (9) —NH—C₁₋₆alkyl, or—N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstituted or substituted withhalogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.
 8. The compound ofclaim 7 wherein R^(1a), R^(1b) and R^(1c) are independently selectedfrom the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl,(4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl or napthyl, and (5) —O—C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl.
 9. Thecompound of claim 8 wherein R^(1a), R^(1b) and R^(1c) are independentlyselected from the group consisting of: (1) hydrogen, (2) chloro, (3)fluroro, and (4) methyl.
 10. The compound of claim 1 wherein R^(2a),R^(2b) and R^(2c) are independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl ornapthyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (6) heteroaryl, wherein heteroaryl isselected from pyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, (7) phenyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, and (9) —NH—C₁₋₆alkyl, or—N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstituted or substituted withhalogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.
 11. The compound ofclaim 10 wherein R^(2a), R^(2b) and R^(2c) are independently selectedfrom the group consisting of: (1) hydrogen, (2) chloro, (3) fluoro, (4)bromo, (5) methoxy, (6) t-butoxy, (7) difluoromethyl, and (8)trifluoromethyl, (9) —N(CH₃).
 12. The compound of claim 1 whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl,which is unsubstituted or substituted with halogen, hydroxyl, phenyl ornapthyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (6) heteroaryl, wherein heteroaryl isselected from pyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, (7) phenyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, and (9) —NH—C₁₋₆alkyl, or—N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstituted or substituted withhalogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂; with the provisothat if A³ is pyridyl, at least one of R^(3a), R^(3b) and R^(3c) isother than hydrogen.
 13. The compound of claim 12 wherein R^(3a), R^(3b)and R^(3c) are independently selected from the group consisting of: (1)hydrogen, (2) halogen, and (3) C₁₋₆alkyl; with the proviso that if A³ ispyridyl, at least one of R^(3a), R^(3b) and R^(3c) is other thanhydrogen.
 14. A compound which is selected from the group consisting of:N-(3,4-Dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-6′-fluoro-2,3′-bipyridine-3-carboxamide;N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-quinolin-3-ylnicotinamide;N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-(3-hydroxyphenyl)nicotinamide;N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-{3-[(methylamino)carbonyl]phenyl}-nicotinamide;N-(3,4-dimethoxybenzyl)-2-{3-[(dimethylamino)methyl]phenyl}-5-(3,5-dimethylphenyl)nicotinamide;N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-(1H-indol-5-yl)nicotinamide;5-(3,5-dimethylphenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(quinolin-2-ylmethyl)nicotinamide;N-[(5,6-dimethoxypyridin-3-yl)methyl]-5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-dichlorophenyl)-N-[(2,3-dimethyl-1H-indol-6-yl)methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3-fluoro-5-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-[(1R)-1-(2-naphthyl)ethyl]nicotinamide;5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(2-naphthylmethyl)nicotinamide;5-(3-fluoro-5-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(2-naphthylmethyl)nicotinamide;5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(quinolin-3-ylmethyl)nicotinamide;5-(3-Chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-fluoromethylphenyl)-N-[1-(3,4-dimethoxyphenyl)ethyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-fluoromethylphenyl)-N-(3,4-dimethoxybenzyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-chloromethylphenyl)-N-[(2,3-dimethyl-1-H-indol-5-yl)methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-chloromethylphenyl)-N-(2-naphthylmethyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-fluoromethylphenyl)-N-(3,4-dimethoxybenzyl)-2-pyridazin-3-yl-nicotinamide;5-(3,5-chloromethylphenyl)-N-(3,4-dichlorobenzyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-fluoromethylphenyl)-N-[1-(3,4-dimethoxyphenyl)ethyl]-6′-fluoro-2,3′-bipyridine-3-carboxamide;5-(3,5-dichlorophenyl)-N-(3,4-dimethoxybenzyl)-5′-chloro-2,3′-bipyridine-3-carboxamide;5-(3,5-chloromethylphenyl)-N-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-chloromethylphenyl)-N-[(1-methyl-2,3-dihydro-1H-indol-5-yl)methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-chloromethylphenyl)-N-[(1,4-dimethyl-1,2,3,4-tetrahydroquinoxalin-6-yl)methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-chloromethylphenyl)-N-[(1,4,5-trimethyl-1H-imidazol-2-yl)methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-fluoromethylphenyl)-N-(3,4-dimethoxybenzyl)-2-(1-methyl-1H-pyrazol-5-yl)nicotinamide;5-(3,5-chloromethylphenyl)-N-(3,4-dihydroxybenzyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3,5-chloromethylphenyl)-N-[(1-methyl-1H-indol-2-yl)methyl]-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide;5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-(morpholin-4-yl)nicotinamide;5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-piperidin-1-ylnicotinamide;5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-pyrrolidin-1-ylnicotinamide;2-azetidin-1-yl-5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-nicotinamide;5-(3,5-dichlorophenyl)-N-(3,4-dimethoxybenzyl)-2-(3-methoxyazetidin-1-yl)nicotinamide;5-(3,5-dichlorophenyl)-N-(3,4-dimethoxybenzyl)-2-(3-fluoroazetidin-1-yl)nicotinamide;5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-[(3R)-3-fluoropyrrolidin-1-yl]nicotinamide;5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-thiomorpholin-4-ylnicotinamide;5-(3,5-dichlorophenyl)-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2-morpholin-4-ylnicotinamide;5′-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-morpholin-4-yl-3,3′-bipyridine-5-carboxamide;N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-6-morpholin-4-yl-3,3′-bipyridine-5-carboxamide;5-(3-chloro-5-methylphenyl)-N-[(5,6-dimethoxypyrazin-2-yl)methyl]-2-morpholin-4-ylnicotinamide;N-[4-methoxy-3-(trifluoromethyl)benzyl]-5′-methyl-6-pyrrolidin-1-yl-3,3′-bipyridine-5-carboxamide;N-(3-chloro-4-methoxybenzyl)-5′-methyl-6-pyrrolidin-1-yl-3,3′-bipyridine-5-carboxamide;5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-N-[(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl]-3,3′-bipyridine-5-carboxamide;N-[(5,6-dimethoxypyridin-2-yl)methyl]-5-(3,5-dimethylphenyl)-2-(4-methyl-1H-pyrazol-1-yl)nicotinamide;5-(3-chloro-5-fluorophenyl)-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2-(4-methyl-1H-pyrazol-1-yl)nicotinamide;N-(3-cyclopropyl-4-methoxybenzyl)-5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxamide;N-(3-chloro-4-methoxybenzyl)-5-(3-fluoro-5-methoxyphenyl)-2-(1H-pyrazol-1-yl)nicotinamide;N-(3-chloro-4-methoxybenzyl)-5′-methyl-6-(1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxamide;N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxamide;N-(3-ethyl-4-methoxybenzyl)-5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxamide;N-(3-chloro-4-methoxybenzyl)-5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxamide;5-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-2-(4-methyl-1H-pyrazol-1-yl)nicotinamide;6-cyclopentyl-N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-3,3′-bipyridine-5-carboxamide;6-cyclopentyl-N-(3,4-dimethoxybenzyl)-5′-methyl-3,3′-bipyridine-5-carboxamide;N-(3-chloro-4-methoxybenzyl)-6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxamide;6-cyclopentyl-N-[4-methoxy-3-(trifluoromethyl)benzyl]-5′-methyl-3,3′-bipyridine-5-carboxamide;or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 16. (canceled) 17.(canceled)
 18. A method for enhancing the quality of sleep in amammalian patient in need thereof which comprises administering to thepatient a therapeutically effective amount of the compound of claim 1 ora pharmaceutically acceptable salt thereof.
 19. A method for treatinginsomnia in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof.
 20. Amethod for treating or controlling obesity in a mammalian patient inneed thereof which comprises administering to the patient atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.